Angiopoietin-like Protein 2 Is a Multistep Regulator of Inflammatory Neovascularization in a Murine Model of Age-related Macular Degeneration.
Angiopoietin-like Protein 2 Is a Multistep Regulator of Inflammatory Neovascularization in a Murine Model of Age-related Macular Degeneration.
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DOI：
10.1074/jbc.m115.710186
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发表时间：
2016-04-01
期刊：
影响因子：
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通讯作者：
Ozawa Y
中科院分区：
文献类型：
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作者：
Hirasawa M;Takubo K;Osada H;Miyake S;Toda E;Endo M;Umezawa K;Tsubota K;Oike Y;Ozawa Y
脉络膜新生血管（CNV）是老年性黄斑变性的一个致病过程，黄斑变性是一种视力威胁疾病。视网膜色素上皮和巨噬细胞都影响CNV的发育。然而，潜在的机制仍然不清楚。在这里，我们关注Angptl2（血管生成素样蛋白2），一种与年龄相关的全身性疾病有关的细胞因子。Angptl2最初被确定为脂肪细胞因子，也在眼睛中表达。通过激光诱导CNV模型，我们发现Angptl2 KO小鼠CNV发育受到抑制，巨噬细胞募集和炎症介质诱导减少。在CNV发育过程中上调的介质单核细胞趋化蛋白-1、白细胞介素-1β (Il-1β)、Il-6、基质金属蛋白酶-9 （Mmp-9）、转化生长因子-β1 （Tgf-β1）在Angptl2 KO小鼠CNV模型的视网膜色素上皮-脉络膜中均受到抑制。野生型和KO小鼠的骨髓移植表明，骨髓源性和宿主源性Angptl2都参与巨噬细胞募集和CNV发育。来自Angptl2 KO小鼠的腹腔巨噬细胞表达较低水平的炎症介质。在野生型腹膜巨噬细胞和RAW264.7细胞中，Angptl2通过整合素α4和β2诱导这些介质，随后下游激活NF-κB和ERK。Angptl2激活NF-κB和ERK也促进巨噬细胞迁移。因此，来自局灶组织的Angptl2可能触发巨噬细胞募集，而来自募集的巨噬细胞的Angptl2可能以自分泌和/或旁分泌的方式促进包括Angptl2在内的炎症介质的表达，从而促进CNV的发展。因此，Angptl2可能代表了CNV发病机制的多步骤调节因子，并可作为年龄相关性黄斑变性的新治疗靶点。
Choroidal neovascularization (CNV) is a pathogenic process of age-related macular degeneration, a vision-threatening disease. The retinal pigment epithelium and macrophages both influence CNV development. However, the underlying mechanisms remain obscure. Here, we focus on Angptl2 (angiopoietin-like protein 2), a cytokine involved in age-related systemic diseases. Angptl2 was originally identified as an adipocytokine and is also expressed in the eye. Using a laser-induced CNV model, we found that Angptl2 KO mice exhibited suppressed CNV development with reduced macrophage recruitment and inflammatory mediator induction. The mediators monocyte chemotactic protein-1, interleukin-1β (Il-1β), Il-6, matrix metalloprotease-9 (Mmp-9), and transforming growth factor-β1 (Tgf-β1) that were up-regulated during CNV development were all suppressed in the retinal pigment epithelium-choroid of CNV models generated in the Angptl2 KO mice. Bone marrow transplantation using wild-type and KO mice suggested that both bone marrow-derived and host-derived Angptl2 were responsible for macrophage recruitment and CNV development. Peritoneal macrophages derived from Angptl2 KO mice expressed lower levels of the inflammatory mediators. In the wild-type peritoneal macrophages and RAW264.7 cells, Angptl2 induced the mediators via integrins α4 and β2, followed by the downstream activation of NF-κB and ERK. The activation of NF-κB and ERK by Angptl2 also promoted macrophage migration. Therefore, Angptl2 from focal tissue might trigger macrophage recruitment, and that from recruited macrophages might promote expression of inflammatory mediators including Angptl2 in an autocrine and/or paracrine fashion to facilitate CNV development. Angptl2 might therefore represent a multistep regulator of CNV pathogenesis and serve as a new therapeutic target for age-related macular degeneration.